Impaired tissue healing is a significant problem in health care. Chronic, non-healing wounds are a major cause of prolonged morbidity in the aged human population. This is especially the case in bedridden or diabetic patients who develop severe, non-healing skin ulcers. In many of these cases, the delay in healing is a result of inadequate blood supply either as a result of continuous pressure or of vascular blockage. Poor capillary circulation due to small artery atherosclerosis or venous stasis contribute to the failure to repair damaged tissue. Such tissues are often infected with microorganisms that proliferate unchallenged by the innate defense systems of the body which require well vascularized tissue to effectively eliminate pathogenic organisms. As a result, most therapeutic intervention centers on restoring blood flow to ischemic tissues thereby allowing nutrients and immunological factors access to the site of the wound.
Wounds (i.e., lacerations or openings) in mammalian tissue result in tissue disruption and coagulation of the microvasculature at the wound face. Repair of such damage represents an orderly, controlled cellular response to injury. All soft tissue wounds, regardless of size, heal in a similar manner. Tissue growth and repair are biologic systems wherein cellular proliferation and angiogenesis occur.
Although many of the basic biochemical steps in wound healing have been characterized, a number of key regulatory factors have yet to be identified. The identification of such factors could lead to improved methods for the treatment of disease states associated with ineffectual wound healing. In wound healing, lymphoid cells release soluble factors that attract fibroblasts and macrophages initiating repair, endothelial cell migration, angiogenesis and matrix production.
An important aspect of wound repair is the revascularization of damaged tissue by angiogenesis. The process of angiogenesis involves endothelial cell attachment, basement membrane degradation and synthesis, migration and proliferation. Mitogenic factors released from lymphoid and endothelial cells can induce angiogenesis and promote neovascularization of damaged tissue. Regulation of angiogenesis is of considerable significance in tissue formation, wound healing and in pathological conditions such as cancer, Wegener's granuloma, Takayasu's arteritis, systemic lupus erythematosus and other autoimmune diseases.
Previous studies have used the "scratch" wound closure assay to assess the potential effects of an agent on in vitro cell migration. Though informative, such a test does not mimic in vivo wound healing conditions to the extent that all factors involved in wound closure are present in the assay. For this reason, in vivo systems have been developed to assess the ability of an agent or factor to modulate wound healing activities.
T.alpha.1 was initially identified as an immunomodulatory factor which affects T-cell maturation, differentiation and function in vitro and in vivo. T.alpha.1 can enhance the production of IL-2 and a-IFN and upregulate the expression of IL-2 receptors on mitogen-stimulated T-cells. In addition, T.alpha.1 has important actions outside the immune system related to a role for this peptide and its 113 amino acid parent molecule, prothymosin .alpha., in regulating cell proliferation and apoptosis (Sburlati et al., Proc. Natl. Acad. Sci. 88:253, 1991).